Project(Summary( Although there has been substantial progress in the development of medications to lower pulmonary vascular resistance in pulmonary arterial hypertension (PAH), there are no therapies that are known to benefit the right heart in the absence of changes in right ventricular afterload. Right heart failure is the key driver for morbidity and mortality in patients with PAH, but also complicates a range of other common diseases such as emphysema and left heart failure. We are pursuing a novel approach that targets histamine H2 receptors in patients with PAH and right heart failure. Previous animal studies suggest myocardial H2 receptors contribute to myocardial fibrosis and are important heart failure mediators. A previous randomized controlled trial showed famotidine improved b-natriuretic peptide, left ventricular morphology, and symptoms in participants with Heart Failure and Reduced Ejection Fraction (left heart failure). Our work has shown differences in right ventricular morphology among community dwelling adults and a lower all-cause mortality in veterans with pulmonary hypertension who use H2 receptor antagonists. These preliminary results raise the strong possibility that H2 receptor antagonism might be an effective treatment for right heart failure. H2 receptor antagonism is an appealing therapeutic target that is well aligned with current NIH priorities of repurposing existing, inexpensive, and well-tolerated medications for novel use in other disease states. Medications for pulmonary arterial hypertension are particularly expensive. If adjunctive therapy with an H2 receptor antagonist is efficacious this would benefit PAH patients and society at-large. We propose a Phase 2, single-center, randomized placebo controlled trial of famotidine (an H2 receptor antagonist) in adults with PAH. The study will evaluate the safety and clinical efficacy of a 24-week course of famotidine. The primary end-point is six-minute walk distance at 24 weeks. Secondary endpoints include differences in right ventricular function, biochemical markers of right heart failure (nt- pro-BNP), New York Heart Association Functional Class, health related quality of life as assessed by the disease specific emPHasis-10 instrument, and the frequency with which routine therapies for patients with PAH are escalated during the trial.